Retroviruses integrate a DNA copy of their genome into host DNA as an obligatory step in their replication cycle. Our work focusses on the molecular mechanism of integration. HIV-1 integrase specifically recognizes and cleaves the viral end DNA during the initial step of retroviral integration. We have used mutational analysis of the viral end LTR sequence, in vitro selection of optimal viral end sequences, and specific photocrosslinking to identify regions of integrase that interact with specific bases in the LTR termini. The results highlight the involvement of the disordered loop of the integrase core domain, specifically residues Q148 and Y143 in binding the terminal portions of the viral DNA ends. In addition, we have identified positions upstream in the LTR termini which interact with the C- terminal domain of integrase, providing evidence that this region of integrase stabilizes binding of the viral DNA ends. On the basis of these results we have made a tentative model of how the terminal viral DNA sequence may interact with integrase We have identified a cellular factor (BAF) that protects MLV preintegration complexes against self-destructive autointegration into its own genome. Preliminary experiments suggest that the non-specific DNA binding properties of this protein serve to compact the viral DNA, thus making it less accessible as a target for integration. We find that BAF is the major DNA binding activity in cytoplasmic extracts of a wide variety of eukaryotic cells. The DNA binding activity of BAF is therefore probably sufficient to account for how it is recruited by the preintegration complex. The solution structure of the BAF dimer has been determined in collaboration with the NMR groups in LCP/ NIDDK and the organization of the BAF/DNA complex is currently under investigation.